Project Summary/Abstract Programmed cell death (PCD) has vital roles in organismal health and is an essential part of normal development. Inappropriate cell survival is a hallmark of tumor progression. Apoptosis is genetically programmed and mutations in regulatory genes contribute greatly to cancer therapy resistance. Timely clearance of cellular debris following cell death is also critical as defects lead to inflammation and are linked to autoimmune disease. Most cells in the body are highly differentiated and have intricate morphologies. This presents challenges in the execution of cell death and clearance, as the subcellular architecture and microenvironment of different regions of the same cell may differ vastly. Complex cells can die as a whole or in part. In the case of region-specific degeneration, cellular extensions, such as axons, are exclusively dismantled leaving the rest of the cell intact. For neurons, such pruning is important in establishing appropriate connectivity and thus for proper brain function. While distinct programs are thought to control the degeneration of different cell regions, the precise cell biological and molecular mechanisms governing compartment-specific destruction are not well understood. Are degenerative mechanisms in each part of the cell inter-related or do they influence one another? What role do caspases, essential executers of apoptosis, play in the different cell compartments? Is the clearance of structurally diverse cell compartments mechanistically similar and mediated by the same canonical engulfment programs? This proposal takes a genetic approach in C. elegans to address these questions in the tail-spike cell, a morphologically complex cell that undergoes PCD during development. Preliminary data demonstrates that the tail-spike cell is an informative model for complex cell degeneration, given its compartment-specific degeneration kinetics and differential genetic regulation at the levels of both killing and clearance. Aim 1 of the project characterizes novel, compartment-specific, functions of CED- 3/caspase. Aim 2 examines how the cell fusion receptor EFF-1 mediates a novel process-specific clearance program. The proposed experiments advance the field in several ways. They demonstrate a new mode of degeneration in complex cells; they identify novel regulators of programmed cell death and clearance; they hold the potential to help devise targeted therapies against cell-death-related disease; and they may broaden our understanding of neurite degeneration and pruning, which are prevalent in development, plasticity, injury and disease of the nervous system.